National Physical Laboratory

Conformational targeting Conformational targeting

Developing molecular platforms for the diagnosis of conformational diseases.

Targeting specific protein conformations can enable the treatment of different deseases. In particular, this capability is important for the diagnosis and therapy of proteopathies - neurodegenerative disorders caused by protein misfolding.

Soluble pre-fibrillar oligomers of a small protein known as β-amyloid accumulate early in the brain and block synaptic plasticity, causing memory deficits and leading to Alzheimer's dementias. Diagnostic tests with the ability to detect and distinguish these misfolded pathologic forms from more benign forms have yet to emerge. Such tests should be performed in serum or even in live cells to make commercial use affordable, but at present there are no molecular platforms that can provide a standard test.

Having the capability to overcome such drawbacks is critical for the early diagnosis of proteopathies. This reseach focuses on nanoscale biomolecular platforms enabling direct capture and detection of toxic β-amyloid oligomers in serum. NPL scientists use specifically engineered nanoprobes which can selectively trap β-amyloid in toxic conformations for subsequent measurements by an array of mass-spectrometry, biophysical and biochemical methods. In parallel, we modulate synergistic interactions of the platforms with prefibrillar and fibrillar aggregates in membrane environmets and empricially review membrane-associated mechanisms applicable to systems of other origins.

3D structure and an atomic force micrograph of Alzheimer’s fibrils

(A) 3D structure (A, 2BEG PDB entry rendered by PyMol) and an atomic force micrograph (B) of Alzheimer’s fibrils.

Relevant publications

Membrane mediated regulation in free peptides of HIV-1 gp41: minimal modulation of the hemifusion phase
Cerasoli E, Ravi J, Gregor CR, Hussain R, Siligardi G, Martyna GJ, Crain J, Ryadnov MG
Phys. Chem. Chem. Phys., 2012, 14, 1277-1285


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